PROJECT SUMMARY Our work and that of others has established that people with lower extremity peripheral artery disease (PAD) have greater functional impairment and faster rates of functional decline than people without PAD. However, few therapies improve functioning or prevent functional decline in people with PAD. Intermittent pneumatic compression (IPC) is a non-invasive intervention, consisting of an air pump inside inflatable cuffs that are wrapped around the feet, ankles, and calves and worn for two hours daily. Every 20 second, the cuffs rapidly inflate, followed by rapid deflation. During deflation, arterial blood return into the arteriovenous pressure gradient generates shear stress and stimulates nitric oxide production. Preliminary evidence suggests that IPC improves lower extremity blood flow and walking endurance in people with PAD and that benefits persist for up to 12 months after intervention completion. However, evidence is limited by small sample sizes, high loss to follow-up, lack of blinding, and lack of sham controls. Clinical practice guidelines do not mention IPC as a therapeutic option in PAD. A definitive randomized trial is needed. Walking exercise is first-line therapy for PAD. However, many PAD patients are unable or unwilling to exercise. Therefore, in people with PAD, we will determine whether IPC augments the benefits of exercise on walking endurance and whether IPC alone improves walking endurance compared to sham control. We will conduct a randomized trial (2 x 2 factorial design) of 230 PAD participants randomized to one of four groups: Group A: IPC + exercise; Group B: IPC + ?no exercise? control; Group C: sham control + exercise; and Group D: sham control + ?no exercise? control. The IPC and sham interventions will be delivered for six months. In our primary specific aims, we will determine whether IPC combined with exercise improves the 6-minute walk at 6-month follow-up compared to exercise alone and whether IPC alone improves the 6-minute walk at 6- month follow-up, compared to sham control. In secondary aims, we will determine whether benefits of IPC persist by re-measuring study outcomes at twelve-month follow-up, six months after the IPC intervention is completed. We will also delineate mechanisms by which IPC affects walking performance, by measuring changes in MRI-measured calf muscle perfusion, physical activity (measured with ActiGraph), and calf muscle biopsy measures of angiogenesis, muscle regeneration, mitochondrial biogenesis, mitochondrial activity, and autophagy. Based on preclinical evidence that IPC increases nitric oxide abundance and promotes vasodilation in skeletal muscle distant from the lower extremities, we will determine whether IPC improves systemic endothelial function, by measuring changes in brachial artery flow-mediated dilation. If the IPC intervention with and without exercise improves functional performance and prevents functional decline in PAD, this non-invasive and well tolerated intervention will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people with PAD.